Abstract C250: Concurrent targeting Bcl-2/Bcl-xL and MDM2 as a new therapeutic strategy for acute leukemia.

Abstract Acquired resistance of tumor cells to anticancer drugs is a major cause of cancer therapy failure in the clinic. In this study, we have investigated the acquired resistance mechanisms in vitro and in vivo for two novel anticancer drugs currently in clinical trials, a Bcl-2/Bcl-xL inhibitor ABT-263 and a MDM2-p53 interaction inhibitor MI-77301/SAR405838. In adult relapsed ALL (RS4;11) xenograft model, both ABT-263 and SAR405838 induced rapid and complete tumor regression but tumors regrew shortly after treatment cessation for both drugs. In pediatric AML (MV4;11) xenograft model, ABT-263 induced tumor growth inhibition and SAR405838 induced rapid and complete tumor regression but tumors also regrew after treatment stopped. Analysis of RS4;11 and MV4;11 resistant tumors to both drugs show that tumor cells evade apoptosis induction by the MDM2 inhibitor by mutation of p53 gene or compromised p53 function, whereas in RS4;11 tumor cells lose their sensitivity to the Bcl-2/Bcl-xL inhibitor through down-regulation of pro-apoptotic Bcl-2 family member BAX. Interestingly, RS4;11 tumors which became resistant to SAR405838, retained sensitivity to ABT-263 and rapid tumor regression was observed upon treatment with ABT-263. Similarly, in both RS4;11 and MV4;11 models, tumor cells which became highly resistant to ABT-263 were still very sensitive to SAR405838 and tumors resistant to the treatment of ABT-263 underwent rapid and complete tumor regression upon treatment with SAR405838. Furthermore, in both leukemia xenograft mouse models, sequential treatment with ABT-263 followed by SAR405838 achieved rapid and complete tumor regression with extended tumor free survival compared to the single agents. Additionally, the combination of SAR405838 and ABT-263 achieved a higher degree of long-term tumor regression than either agent alone. Our study provides new insights into the resistant mechanisms for both Bcl-2/Bcl-xL and MDM2 inhibitors in acute leukemia. Importantly, our preclinical data suggest that the combination and sequential treatment of these two distinct classes of novel apoptosis-inducing agents should be explored as an innovative treatment strategy for acute leukemia in the clinic with the goal to overcome acquired drug resistance and to improve the long-term clinical outcome for acute leukemia patients. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C250. Citation Format: C. Gianna Hoffman-Luca, Donna McEachern, Daniel Ziazadeh, Yu-Jun Zhao, Wei Sun, Laurent Debussche, Shaomeng Wang. Concurrent targeting Bcl-2/Bcl-xL and MDM2 as a new therapeutic strategy for acute leukemia. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C250.